Composition for suppressing withdrawal symptoms and craving for alcohol in alcoholics and preventing the abuse of alcohol in healthy subjects

ABSTRACT

A combination composition comprising L-carnitine, acetyl L-carnitine and propionyl L-carnitine or the pharmacologically acceptable salts thereof is disclosed which can be used as a pharmaceutical composition for suppressing withdrawal symptoms and craving for alcohol in alcoholics, and as a dietary supplement, health food, medical food or nutraceutical for preventing the abuse of alcohol in substantially healthy subjects, particularly in young individuals.

This application is a 35 U.S.C. § 371 of PCT/IT98/00249, filed Sep. 18,1998.

The present invention relates to a combination composition ofL-carnitine and lower alkanoyl L-carnitines or the pharmacologicallyacceptable salts thereof for the treatment of alcoholism. The use of thecombination composition suppresses withdrawal symptoms (such as tremors,perspiration, hyperreflexia, nausea, anxiety and convulsions) and thecraving for alcohol.

All the drugs used to date for the treatment of alcoholism presentsubstantial drawbacks.

A number of the drugs commonly used in the treatment of alcoholwithdrawal syndrome are similar to this with regard to theirpharmacological effects. In fact, the most useful of those currentlyused are those with which alcohol develops a cross-tolerance. Allpatients treated for withdrawal syndromes are potential candidates forSNC depressants though not all of them need them.

Paraldehyde, which was once extensively used in therapy, was completelyabandoned on account of its disagreeable odour and a series of sudden,inexplicable deaths following its use.

Rarely used today is the fast-acting barbiturate (pentobarbital andsecobarbital).

The drugs of choice are benzodiazepines such as chlorodiazepoxide anddiazepam. One serious drawback they present, however, is the fact thatalcoholics taking chlordiazepoxide or diazepam may become intoxicatedand even develop physical addiction and withdrawal syndrome.

The phenothiazines are not recommended since they do not control severedelirium tremens and also lower the threshold for attacks of epilepsy.

Lastly, a matter of some controversy is the therapeutic use ofdisulfiram which interferes with the metabolism of acetaldehyde (anintermediate product of the oxidation of alcohol) and produces anaccumulation of it, thus causing toxic symptoms and severe discomfort.Drinking alcohol within 12 hours of taking disulfiram produces facialflushing within 5-15 minutes, followed by intense vasodilatation of theface and neck with clouding of the conjunctiva, throbbing headache,tachycardia, hyperpnoea and perspiration. Within 30-60 minutes nauseaand vomiting appear and can be so intense as to lead to hypertension,dizziness and sometimes fainting or collapse. The reaction lasts fromone to three hours. The sense of malaise is so intense that few patientswill risk drinking alcohol while taking disulfiram. Occasionally, thisdrug has also caused convulsions, cardiac arrhythmias and myocardialinfarction.

The efficacy of carnitine in decreasing the withdrawal symptoms in testanimals has been reported.

Abu Murad et al. (Brit. J. Pathol. vol. 58. n. 6, Dec. 1977) disclosesthat in mice “the addition of DL-carnitine to diet during theadministration of ethanol . . . significantly reduced the intensity ofthe ethanol withdrawal syndrome”.

Corbett et al. (Neuropharmacology, vol. 23, n. 2B, pp. 269-271, 1984)postulate that carnitine administration can counteract “at least some ofthe effects of prolonged administration and withdrawal of ethanol . . .by preventing the alcohol-induced change in the activity of(calcium/magnesium) ATPase”.

As regards acetyl L-carnitine, Tempesta et al. (Int. J. Clin. Pharm.Res. X (1/2) 101-107, 1990) report preliminary data from a multicentreddouble-blind placebo-controlled study which suggest a possible efficacyof acetyl L-carnitine in decreasing some cognitive deficits in at leastone month-abstinent chronic alcoholics.

The efficacy of other alkanoyl L-carnitines, particularly propionylL-carnitine, in the treatment of alcoholics, has never been postulatednor tested.

It has now been found that a combination composition comprisingL-carnitine, acetyl L-carnitine, propionyl L-carnitine or thepharmacologically acceptable salts thereof not only suppresses thewithdrawal symptoms (such as tremors, perspiration, hyperreflexia,nausea, anxiety and convulsions) and the craving for alcohol inalcoholics, but can also be used effectively as a preventive orprophylactic means in substantially healthy subjects who, however,overindulge in an excessive, although occasional and discontinuous,intake of alcoholic drinks.

It is worth noticing that the users of the compositions of the presentinvention may also be substantially healthy individuals, particularlyyoung subjects, who, although they cannot be clinically regarded asalcohol-addicted, occasionally indulge in an excessive intake ofstrongly alcoholic drinks under circumstances which take place morefrequently than in the past, as a consequence of the profound changes inlifestyle which have occurred, particularly with regard to youngindividuals, over a relatively short space of time. This phenomenon canaffect important aspects of family life as well as social and personalrelations, with worrying consequences even of a socio-economic nature.

The combination compositions of the present invention can, therefore,occur not only as pharmaceutical compositions but also as dietarysupplements, health foods, medical foods or nutraceuticals or ascomponents of the aforesaid products. Then, the compositions may alsocomprise, in admixture with L-carnitine and the aforesaid alkanoylL-carnitines, further active ingredients, such as dietary supplements,vitamins, co-enzymes, minerals and the like.

The molar ratio L-carnitine/acetyl L-carnitine/propionyl L-carnitine orthe pharmacologically acceptable salts thereof ranges from 6:4:1 to3:2:1. Preferable, this ratio is 5:4:1.

In unit dosage forms, the compositions comprise 0.44 to 0.66 g ofL-carnitine inner salt; 0.44 to 0.66 g of acetyl L-carnitine inner salt;and 0.12 to 0.18 g of propionyl L-carnitine inner salt or equimolaramounts of their pharmacologically acceptable salts.

What is meant by pharmacologically acceptable salt of L-carnitine,acetyl L-carnitine and propionyl L-carnitine is any salt of these activeingredients with an acid that does not give rise to unwanted toxic orside effects. These acids are well known to pharmacy experts.

Non-limiting examples of suitable salts are the following: chloride;bromide; iodide; aspartate, particularly acid aspartate; citrate,particularly acid citrate; tartrate; phosphate, particularly acidphosphate; fumarate, particularly acid fumarate; glycerophosphate;glucose phosphate; lactate; maleate, particularly acid maleate; orotate;oxalate, particularly acid oxalate; sulphate, particularly acidsulphate; trichloroacetate; trifluoroacetate and methanesulphonate.

A list of FDA-approved pharmacologically acceptable salts is given inInt. J. of Pharm. 33, (1986), 201-217; this latter publication isincorporated herein by reference.

Since L-carnitine and the aforesaid alkanoyl L-carnitine are practicallyatoxic, the combination composition of the present invention does notbring about any of the previously mentioned unwanted toxic or sideeffects.

Reported here below are details of a number in-vivo pharmacologicalstudies which demonstrate the activity of the combination composition ofthe present invention, vis-a-vis L-carnitine and acetyl L-carnitinetaken singularly.

In the following description “COMP” stands for the combinationcomposition, “LC” for L-carnitine, “ALC” for acetyl L-carnitine and“PLC” for propionyl L-carnitine.

Sedative Action COMP in Alcohol-Dependent Rats as Measured According tothe Vogel Test.

Wistar male rats (housed in groups of 5 per cage) were used, kept inconditions of constant light-dark alteration at 21° C. and fed withstandard laboratory feed. The animals were chronically administered 10%ethanol ad lib. for 6 months.

To assess the activity, if any, of COMP on the anxiety componentinvolved in the compulsive act of searching for alcohol, a modifiedversion of the Vogel test was used as described by Keppler D. et al. inExp. Mol. Path. 9, 279 (1968).

Prior to the start of the experiment the animals were deprived of waterfor 48 hours. At the time of ethanol treatment suspension, the animalswere divided into 4 groups who were given the following intraperitonealadministrations: the first group (A) received saline solution (15ml/kg), the second group (B) COMP (20 mg LC+20 mg ALC+4 mg PLC/kg), thethird group (C) LC (20 mg/kg) and the fourth group (D) ALC (20 mg/kg).

On the day of the test, the animals were provided with two drinkingvessels, one containing water and the other a mixture of water andethanol (90:10 v/v) in bottles, the metal spouts of which were connectedup to a source of electricity: after every 5 licks at the drinkingvessel, and electric shock (1 mA) was delivered for 10 min. whichobliged the animal to withdraw, overcoming its desire to drink thewater-alcohol solution. Refusal of the animal to drink the water-alcoholsolution, confining their attention only to the vessel containing wateralone, was taken as an indication of efficacy. In evaluating theresults, the numbers of licks were compared for treated animals versuscontrols over the 10 min. exposure period. The results are given herebelow in Table 1.

TABLE 1 Number of licks of treated animals over 10 min. exposure periodAnimal group Number of licks A (saline) 39.8 ± 7.5 B (COMP)   4.9 ±1.14* C (LC)   10 ± 6.4* D (ALC) 32.2 ± 6.4 *P < 0.01 vs A P < 0.05 vs B

Effects of COMP on Withdrawal Syndrome in Rats as Measured by theHunt-Majchrowicz Method.

The experiment was performed in Wistar male rats housed in groups of 5per cage under conditions of constant light-dark alternation at 21° C.and fed with standard laboratory feed. The animals were chronicallyadministered 10% ethanol ad lib. for 6 months.

Eight hours after suspension of ethanol administration, the animals weredivided into 4 groups of 5 rats each.

The first group (A) was administered saline solution intraperitoneally(15 ml/kg), the second group (B) was given COMP. (20 mg LC+20 mg ALC+4mg PLC/kg), again intraperitoneally, the third group (C) received LC (20mg/kg), while he fourth group (D) was given ALC (20 mg/kg). For thepurposes of assessing the effects induced by the above-mentionedtreatments on occurrence of alcohol withdrawal syndrome, tremors weremeasured in the rat, where, as in man, they are the most characteristicsign of withdrawal syndrome. Evaluation of the number of tremors wasdone using the method described by Hunt and Majchrowicz [see Hunt W. A.and Majchrowicz E., Journal of Pharmacology and ExperimentalTherapeutics, 213, 9-12 (1980)]. The results are given here below inTable 2.

TABLE 2 Animal group 30 min. 60 min. 90 min. l20 min. A (saline) 6 ± 1.59 ± 2.5 8 ± 2.5 9 ± 1.5 B (COMP) 0 ± 0.25 0 ± 0 0 ± 0.65 0 ± 0.25 C (LC)2 ± 0.5 1 ± 0.5 2 ± 1 3 ± 1 D (ALC) 4 ± 2 5 ± 2 5 ± 1.5 6 ± 2

Effects of COMP on withdrawal syndrome as assessed by observingbehaviour of rats chronically treated with alcohol when subjected tosound stimulation.

The experiment was performed in Wistar male rats housed in groups of 5per cage under constant light-dark alternation at 21° C. and fed withstandard laboratory feed. The animals were chronically administered 10%ethanol ad lib. for 6 months.

Eight hours after suspension of ethanol administration the animals weredivided into 4 groups of 10 rats each.

The first group (A) were administered saline solution (15 ml/kg)intraperitoneally, the second group (B) COMP (20 mg LC+20 mg ALC+4 mgPCL/kg) again intraperitoneally, the third group (C) LC (20 mg/kg) andthe last group (D) ALC (20 mg/kg). For the purposes of evaluating theeffects of the treatment on occurrence of alcohol withdrawal syndrome,the rats' susceptibility to onset of behavioural reactions (convulsions)due to emission of sound for 1 min. by an electric bell (100 dB) wasobserved. The experiment was performed in all groups of rats one hourafter treatment, and the results are given here below in Table 3.

TABLE 3 Animals with convulsions/ Animal group animals treated A(saline) 8/10 B (COMP) 1/10 C (LC) 5/10 D (ALC) 6/10

Effects of COMP on lipoperoxidation in the CNS of rats receiving chronicethanol treatment.

This study was conducted in order to assess what variations inmalonaldehyde (MDA) occur following COMP administration, MDA being areliable and quantifiable index of the vulnerability of the centralnervous system to damage due to free radicals as a result of thedetrimental effect of ethanol.

The experiment was conducted in Wistar male rats housed in group of 5per cage under constant light-dark alternation at 21° C. and fed withstandard laboratory feed. Two groups of rats, each comprising 5 animals,were administered 10% ethanol in water throughout the treatment period.A third group of animals was kept on a standard laboratory diet withoutreceiving any treatment. After two months of ethanol treatment, theanimals in the first group were administered COMP (20 mg LC+20 mg ALC+4mg PLC/kg) in a single intraperitoneal dose. A few hours aftertreatment, the animals were sacrificed and the brains promptly removed.MDA was measured using a modified micromethod described by Slater andSawyer (Slater T. F. and Sawyer B. C., 1971, J. Biochem. Tokyo 8: 2180).The tissue was held for 10 min. at 0° C. in Tris-HCl 0.05 M buffer at pH7.4 and then homogenized. An aliquot (0.05 ml) of cerebral homogenatewas extracted with 20% trichloroacetic acid (w/v). After centrifuging,0.9 ml of supernatant were added to 1 ml of 0.67% thiobarbituric acid inTris-HCl 0.026 M buffer at pH 7.0. The samples were placed in boilingwater for 10 minutes and after cooling absorbance was determined at 532nm using a spectrophotometer. MDA was expressed in nmol/mg protein.Proteins were measured by the Smith method (Smith at al., 1985, Analyt.Biochem. 27: 502), using bicinchoninic acid as reagent. Table 4 herebelow shows the amount of MDA in control animals, in animals afteradministration of ethanol and in animals after administration ofethanol+COMP.

TABLE 4 MDA Animal group nmol/mg protein Control 0.543 ± 0.19 Ethanol 1.12 ± 0.13 Ethanol + COMP. 0.385 ± 0.15

The composition of the present invention can be administered orally orparenterally, in any of the usual pharmaceutical forms which areprepared by conventional procedures well-known to the experts in thesetechniques. These forms comprise oral unit dosage forms, both liquid andsolid, such as tablets, capsules, solutions, syrups and the like, andinjectable forms such as, for example, sterile solutions for vials andampoules.

For these pharmaceutical forms the usual solvents, diluents andexcipients are used. Optionally, preservative, sweetening and flavouringagents can be added. Non-limiting examples of such substances are sodiumcarboxymethyl cellulose, polysorbate, sorbitol, starch avicel, talc andothers which are evident to experts in pharmaceutical technology.

What is claimed is:
 1. An orally or parenterally administrablecomposition comprising in admixture L-carnitine, acetyl L-carnitine andpropionyl L-carnitine or the pharmacologically acceptable salt thereof.2. The composition of claim 1 as a dietary supplement, health food,medical food, nutraceutical or component thereof for preventing theabuse of alcohol in substantially healthy subjects.
 3. The compositionof claim 1, wherein the molar ratio L-carnitine:acetylL-carnitine:propionyl L-carnitine or the pharmacologically acceptablesalts thereof ranges from 6:4:1 to 3:2:1.
 4. The composition of claim 3wherein said ratio is 5:4:1.
 5. The composition of claim 3 in unitdosage form comprising from 0.44 to 0.66 g L-carnitine inner salt; 0.44to 0.66 g of acetyl L-carnitine inner salt; and from 0.12 to 0.18 g ofpropionyl L-carnitine inner salt or equimolar amounts of thepharmacologically acceptable salts thereof.
 6. The composition of claim1 wherein the pharmacologically acceptable salt of L-carnitine, acetylL-carnitine and propionyl L-carnitine is selected from group comprising:chloride; bromide; iodide; aspartate, particularly acid aspartate;citrate, particularly acid citrate; tartrate; phosphate, particularlyacid phosphate, fumarate particularly acid fumarate; glycerophosphate;glucose phosphate, lactate; maleate, particularly acid maleate; orotate;oxalate, particularly acid oxalate; sulphate, particularly acidsulphate; trichloroacetate, trifluoroacetate and methanesulphonate. 7.The composition of claim 1 further including food supplements, vitamins,co-enzymes and mineral substances.
 8. A method of suppressing withdrawalsymptoms and the craving for alcohol comprising administering to anindividual an effective amount of a combination of L-carnitine, acetylL-carnitine and propionyl L-carnitine or the pharmacologicallyacceptable salts thereof.
 9. A method of preventing the abuse of alcoholin substantially healthy individuals, said method comprisingadministering to an individual an effective amount of a combination ofL-carnitine, acetyl L-carnitine and propionyl L-carnitine or thepharmacologically acceptable salts thereof.
 10. The method of claim 8 or9 wherein the molar ratio L-carnitine:acetyl L-carnitine:propionylL-carnitine or the pharmacologically acceptable salts thereof rangesfrom 6:4:1 to 3:2:1.
 11. The method of claim 10, wherein the molar ratiois 5:4:1.
 12. The method of claim 8 or 9 wherein a unit dosage isadministered comprising from 0.44 to 0.66 g L-carnitine inner salt; 0.44to 0.66 g of acetyl L-carnitine inner salt; and from 0.12 to 0.18 g ofpropionyl L-carnitine inner salt or equimolar amounts of thepharmacologically acceptable salts thereof.
 13. The method of claim 8 or9 wherein the pharmacologically acceptable salt of L-carnitine, acetylL-carnitine and propionyl L-carnitine is selected from group consistingof chloride, bromide, iodide, aspartate, citrate, tartrate, phosphate,fumarate, glycerophosphate, glucose phosphate, lactate, maleate,orotate, oxalate, sulphate, trichloroacetate, trifluoroacetate andmethanesulphonate.